title: Structural analysis of spiro beta-lactone proteasome inhibitors.
abstract: Spiro beta-lactone-based proteasome inhibitors were discovered in the context of an asymmetric catalytic total synthesis of the natural product (+)-lactacystin (1). Lactone 4 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer (5) displayed weak activity. Crystallographic studies of the two analogues covalently bound to the 20S proteasome permitted characterization of the important stabilizing interactions between each inhibitor and the proteasome's key catalytic N-terminal threonine residue. This structural data support the hypothesis that the discrepancy in potency between 4 and 5 may be due to differences in the hydrolytic stabilities of the resulting acyl enzyme complexes.
authors.affiliation: Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
authors.forename: Emily P
authors.initials: EP
authors.lastname: Balskus
authors.forename: Eric N
authors.initials: EN
authors.lastname: Jacobsen
mesh_terms: D018360:Crystallography, X-Ray; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007783:Lactones; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D013141:Spiro Compounds; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease